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THESIS

 

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ABSTRACT

CHANGES IN CANINE FORELIMB COLLATERAL VESSEL RESISTANCE
AFTER ACUTE BRACHIAL ARTERY OCCLUSION AND THE EFFECTS OF
VASODILATOR DRUGS 0N BLOOD FLOW THROUGH THESE COLLATERAL VESSELS

By
Daniel Philip Radawski

The purpose of this study was to determine the changes in the
resistance to blood flow through collateral vessels in the canine
forelimb immediately after acute arterial ligation and to estab-
lish the effects of vasodilator drug administration by two routes
on blood flow through the collateral vessels. This was accomplished
in the following manner. The brachial artery was acutely ligated
while continuously monitoring systemic arterial blood pressure and
brachial artery pressure distal to the occlusion site; five second
serial blood flows were collected from the cannulated brachial and
cephalic veins in graduated cylinders. Vasodilator agents (papav-
erine, Priscoline, Arlidin, acetylcholine) were then given intra-
brachially and intravenously in random sequence at progressively
faster infusion rates. Collateral resistance was calculated by
the formula systemic pressure - distal brachial artery pressure/
total flow. Distal resistances in skin and muscle were calculated
by dividing the distal brachial artery pressure by the appropriate

flow.

Daniel Philip Radawski

The effects of acute ligation of the brachial artery were
an immediate decrease in distal brachial and cephalic resistances
as well as a decrease in collateral vessel resistance from 15 to
74 seconds after occlusion. The salient findings with regard to
vasodilator drug infusion were: 1) an increase in muscle vein
outflow during intravenous infusion of Priscoline but no effect.
on muscle or skin flow with other tested drugs, 2) an increase
in muscle vein outflow during infusion of papaverine, acetyl-
choline and Arlidin and a fall in skin blood flow during intra-
brachial Priscoline infusion, and 3) a fall in distal resistances
without changes in collateral resistance during infusion of the
agents.

This study demonstrates that collateral vessel resistance
decreases from 15 to 74 seconds after ligation. It also shows
that the route of administration is important when vasodilator
drugs are employed to increase canine forelimb collateral blood

flow around an acutely ligated cognate artery.

CHANGES IN CANINE FORELIMB COLLATERAL VESSEL RESISTANCE AFTER
ACUTE BRACHIAL ARTERY OCCLUSION AND THE EFFECTS OF VASODILATOR
DRUGS ON BLOOD FLOW THROUGH THESE COLLATERAL VESSELS

By

Daniel Philip Radawski

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE

Department of Physiology

1969

DEDICATION

TO MY WIFE MARY JO.

ii

ACKNOWLEDGEMENTS

The author wishes to express his sincere appreciation to
Drs. F.J. Haddy, R.M. Daugherty, Jr., and J.B. Scott for their
assistance, concern, and encouragement during the course of his
M.S. program.

The author is also indebted to the members of his guidance
committee and Mr. S. Swindall and Miss S. Krieger for their time
and interest in his behalf.

111

TABLE OF CONTENTS

DEDICATION ........................... 11
ACKNOWLEDGEMENTS ......................... 111
LIST OF TABLES ......................... v
LIST OF FIGURES ......................... vi
Chapters
1. SURVEY OF THE LITERATURE ................ I
Introduction . . . ................... l
Collateral Circulation and Ligation ........... 1
Methods of Increasing Flow ............... 6

Intravenous and Intra-arterial Routes of Administration . 10

II. METHODS ......................... 15
III. RESULTS ......................... 19
IV. DISCUSSION ....................... 38
Collateral Circulation and Ligation ........... 39
Vasodilator Drug Infusion ................ 42

V. SUMMARY AND CONCLUSIONS ................. 49
BIBLIOGRAPHY ........ . ................. 51
APPENDIX ................. - ........... 55

iv

LIST OF TABLES

Table Page
1. Classification of vasodilator drugs ......... 9
2. Average effects of acute brachial artery

occlusion on forelimb vasculature ......... 20
3. Effect of vasodilators on brachial,

cephalic and total flows in the forelimb

after acute arterial occlusion .......... 36

LIST OF FIGURES

Figure Page
1. Diagram of the arteries of the right
antebrachium, medial aspect ............. 3
2. Forelimb preparation ................ 16
3. Typical brachial artery pressure tracing
before and immediately after brachial
artery occlusion .................. 21
4. Average effects of a continuous intravenous
infusion of Priscoline . . . . . . . . ....... 23
5. Average effects of a continuous intrabrachial
infusion of Priscoline ........ . ...... 25
6. Average effects of a continuous intravenous
infusion of Papaverine ............... 26
7. Average effects of a continuous intrabrachial
infusion of Papaverine ............... 28
8. Average effects of a continuous intravenous
infusion of Arlidin ................. 30
9. Average effects of a continuous intrabrachial
infusion of Arlidin . . . . ............. 31
10. Average effects of a continuous intravenous
infusion of Acetylcholine .............. 33
11. Average effects of a continuous intrabrachial
infusion of Acetylcholine ...... . ....... 34

vi

 

SURVEY OF THE LITERATURE

Introduction

When the arterial blood supply to an extremity is decreased due
to total acute arterial occlusion, the collateral circulation is
essential for maintaining flow to preserve the limb. Sudden total
occlusion of a major artery in an extremity produces changes in the
pattern of flow and places great emphasis on the collateral circu-
lation which is normally present in a limb. Blood flow to the
extremity may not return to pre-occlusion levels after total arterial
occlusion (40)(4l) and in many instances may not be sufficient to
sustain normal activity and viability of the extremity. Therefore,
many methods have been employed to increase flow or to increase
the efficiency of exiSting flow (23) around an occluded artery.

The purpose of the paper is to study two phenomena in the dog
forelimb after acute brachial artery occlusion: first, to establish
the level of resistance and to elucidate any resistance changes
which may occur in the collateral vessels around the occlusion in
the first few minutes after blockage; and, second to compare the
effects of systemically and locally administered vasodilatory
compounds on forelimb muscle and skin blood flow after acute

occlusion of the brachial artery.

Collateral Circulation and Ligation
Collateral circulation may be defined as blood flow that pursues

a channel or system of vessels which is alternate to, or develops in
1

substitution for, a major vascular pathway (30). There are two types
of collateral circulations (29). The first is one in which blood
reaches the area beyond an obstruction via terminal branches arising
from another cognate artery, eg. the superficial brain vasculature.
The second type of collateral circulation is one in which blood
reaches the area beyond an obstruction via vessels which diverge
upstream and reanastomose downstream to the occlusion in an artery.
A typical collateral circulation pattern of the latter type is
shown in the diagram of the dog forelimb in figure 1 (35). Note
the abundance of vessels which freely and repeatedly anastomose
with the brachial artery. In the normal animal a greater propor-
tion of flow may be through the brachial artery (44). However,
microscopic and visual experiments have shown that after acute
arterial occlusion the pattern of flow is somewhat different.
Nothnagel (37) microscopically demonstrated in the chick embryo
that shortly after arterial occlusion the anastomotic channels
began to dilate. Roy (41) ligated an artery in the hamster cheek
pouch and microscopically observed the direction of flow. Within
30 seconds after ligation the flow was directed to new, previously
unopened arterial channels around the ligation. Roy's observations
agree with the gross observations of Reichert (39) who indirectly
noted the changes in the flow pattern of the dog aorta and its
collateral vessels. It is interesting to note that in long term
studies Roy observed that no additional vessels opened and no

further development in vessel size occurred.

 

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Few studies have been done concerning the changes in pressure,
flow and collateral vessel resistance (systemic pressure - distal
artery pressure/flow) which occur immediately after acute arterial
occlusion. Also, the mechanism or mechanisms that produce the
changes in collateral vessel resistance have not been fully elucidated.

Winblad gt, 31, (47) reported that acute femoral artery occlusion
in the dog produced an immediate drop in downstream anterior tibial
artery pressure to between 35 and 60 mm Hg. Anterior tibial artery
pressure subsequently returned to approximately 80 mm Hg in 2 to 8
minutes and remained constant for 4 months of observation. John and
Warren (22) observed similar changes in pressure distal to a canine
femoral artery occlusion. These authors noted that anterior tibial
artery pressure fell from between 100 and 150 mm Hg to between 20
and 60 mm Hg, then began to rise in three seconds and in about 3
minutes reached 30-50% of the preocclusion levels. John and Warren
also measured hindlimb blood flow with a venous occlusion plethys-
mograph. However, they did not record the changes in blood flow
which occurred in the first five minutes after occlusion.

Thulesius (44) reported that collateral vessel resistance
decreased immediately after acute femoral artery occlusion in
anesthetized cats. He found that immediately following occlusion
of the femoral artery, pressure and flow distal to the occlusion
decreased for 15 seconds. This initial decrease was followed by
an increase in distal pressure and flow indicating a decrease in

collateral vessel resistance. The response was not affected by

sympathetic blocking agents or by lumbar sympathectomy. Rosenthal
and Guyton (40) also observed a decrease in collateral vessel
resistance in the dog hindlimb immediately after acute arterial
occlusion. They observed an average reduction of distal tibial
artery pressure and flow to 28% and 21% respectively of the control
values in 14 seconds after occlusion. Distal artery pressure and
flow then rose in the first minute to 53% and 58% respectively of
the control levels. Rosenthal and Guyton also demonstrated that
this response occurs in the absence of extrinsic neural influences.
Thulesius and Folkow (12) attributed the decrease in collateral
resistance to an ascending vasodilation. Folkow speculated that
there is a compensatory dilation occurring in the resistance and
precapillary sections distal to the occlusion due to ischemia
and lowered transmural pressure. He believes that this compen-
satory dilation spreads proximally by a vascular smooth muscle
cell to cell propagation of activity such as that described by
Hilton (21) in the femoral artery. Rosenthal and Guyton proposed
other possible mechanisms which may be responsible for the decrease
in collateral resistance seen immediately after acute femoral
artery occlusion. They speculated that the reverse Bayliss
response (i.e., a relaxation in response to a decrease in intra-
luminal pressure) could be involved in these resistance changes.
However, they favor another mechanism. They believe that collateral
vessel resistance may decrease due to a decreased oxygen tension
and/or increased amount of vasodilator substances in the tissues

surrounding the collateral vessels after ligation. In some of

their experiments they preceded ligation by hypotension and they

did not observe any decrease in local collateral vessel resistance
after ligation. They believe that this observation lends credence
to the fact that chemical stimuli may influence collateral vessel
caliber. Other evidence that the collateral vessel resistance can
be affected by local regulatory influences has been demonstrated

by Coffman (6), who found that the venous outflow increased and
collateral resistance decreased during local exercise in the dog
hindlimb and forelimb in which the main arterial supply was acutely
interrupted. Thus, active hyperemia seems to occur in the collateral

vessels of the acutely ligated canine limb.

Methods of Increasing Flow

Blood flow through an extremity is immediately determined by
the pressure gradient across the extremity and the resistance to
flow. An increase in the pressure gradient with no change in the
resistance to flow will increase the flow through the limb; the
same occurs with a decrease in resistance to flow with no concom-
itant alteration in the pressure gradient.

There are several possible methods of increasing blood flow
to a limb whose arterial supply has been suddenly occluded.
Generally, they fall into two categories: 1) an increase in
the perfusion pressure associated with a decrease or no change
in resistance; 2) a decrease in resistance to flow in the affected
limb; either by an increase in caliber or a decrease in blood

viscosity. In addition, various combinations of these two methods

may be employed to increase blood flow. A method by which an
increase in pressure may be obtained is by long-term administration
of mineralo-corticoids (28). Decreases in resistance which increase
flow may occur in different vascular segments of the vascular bed
in which the cognate artery is occluded. Arterial graft reduces
resistance in the occluded vessel while sympathectomy, vasodilatory
drugs, and an increase in ambient temperature affect resistance in
the collateral vessels and/or in the vessels distal to the occlusion.
Exercise is an example of a condition which decreases peripheral
resistance and it may also increase the driving pressure (17).
Arterial graft and sympathectomy have been utilized in humans
as therapy for acute arterial occlusion. There is no doubt as to
the efficiency of arterial graft. However, sympathectomy produces
an increase in flow in the occluded limb which appears to be limited
in duration (ll)(42). Increasing the ambient temperature around
the limb (2) may be effective in increasing blood flow to the limb.
However, if reflex vasodilation associated with hyperthermia is
primarily in the skin (3), then flow through the muscle may not
be altered. Hence, there may not be sufficient flow for mainten-
ance of the muscular tissue at rest or in exercise. Whole body
exercise has also been recommended for clinical treatment in
occlusive arterial disease (27). Theoretically, exercise may be
detrimental in occlusive arterial disease. If the ratio of oxygen
delivery to oxygen utilization is altered such that more oxygen
is required than can be delivered because of the impaired flow

then hypoxia of the tissues during exercise may result. 0n the

8

other hand, moderate exercise may stimulate collateral vessel
growth (26).

Another widely used procedure for increasing collateral flow
around an acutely occluded artery is administration of vasodilator
drugs. These agents offer an easy and expedient means of attempting
to increase blood flow in an ischemic extremity. Vasodilator com-
pounds that are employed to increase flow around an acute peripheral
arterial occlusion can be classified into two main groups according
to the site of action (45): 1) those agents which affect the
autonomic nervous system; and 2) those which act directly on the
blood vessels. The drugs acting on the autonomic nervous system
may be further divided into three subgroups: l) centrally acting
agents, 2) ganglion blocking agents; and 3) those drugs which act
peripherally (table 1). Peripheral acting autonomic drugs may be
a-adrenergic blocking agents or B-adrenergic stimulants. Other
drugs act directly on the vascular smooth muscle. The agents which
are most commonly used in the treatment of acute peripheral blockage
either act directly by relaxing the vascular smooth muscle or they
indirectly affect the vascular smooth muscle by altering peripheral
autonomic nervous system activity. At least one of these agents,
Priscoline, may affect smooth muscle both directly and indirectly (16).

When administering vasodilator drugs it may be important to
consider the skin and skeletal muscle blood flow and the metabolic
rate of these tissues. At rest a 63 Kg man whose metabolic rate

is 280 ml/min and whose cardiac output is 6 1/min will have a blood

 

TABLE 1

Classification of
vasodilator drugs

 

 

Site of Action

Agent

 

I. Autonomic Nervous System
A. Centrally acting

B. Ganglion acting

C. Peripheral acting
l. Adrenolytic

2. Beta stimulatory

II. Smooth Muscle Relaxants

Rauwolfia compounts
Dihydroergot alkaloids
(Hydergine)

Hexamethonium

Pentolinium

Mecamylamine
Trimethidinium
Chlorisondamine

Tetra ethyl ammonium (TEA)
Pempidine

Trimethaphan

Phentolamine (Regitine)

Phenoxybenzamine (Diben-
zyline)

Tolazoline (Priscoline)

Azapetine (Ilidar)

Dihydroergot alkaloids

Nylidrin hydrochloride
(Arlidin)
Isoxsuprine (Vasodilan)

Histamine

Papaverine

Nicotinic acid (Niacin
Tolazoline (Priscoline
Nitrites

Acetylcholine

 

 

10

flow of 31 ml/min/Kg hi skeletal muscle and 133 ml/min/Kg in the
skin. Furthermore, his oxygen consumption will be 1.8 ml/min/Kg
in the skeletal muscle and 3.3 ml/min/Kg in the skin (4). His
flow to metabolic rate ratio will be 1.7 for muscle and 40.3 for
the skin. That is, his skeletal muscle will be underperfused
relative to his skin. Exercise increases the blood flow and
metabolism of the skeletal muscle and it may increase blood flow
through the skin. However, after acute arterial occlusion, blood
flow in the occluded extremity may not be able to increase suf-
ficiently to meet the demands of an increased metabolism. In
this situation the aim of vasodilator drug administration should
be to increase muscle blood flow proportionally more than skin

blood flow.

Intravenous and Intra-arterial Routes of Administration

It has recently been demonstrated that the route of admini-
stration of vasoactive agents isimportant in determining their
effect on local circulation (7). There are two routes of admini-
stration of vasoactive agents; systemic (intravenous, subcutaneous,
oral, intramuscular, intraperitoneal), and local (intra-arterial,
topical). The author is not aware of any studies in the same
experimental animal which systematically compare the systemic
(intravenous) and local (intra-arterial) effect of vasodilator
agents in the acutely occluded limb. Studies of intravenous
administration of vasodilator agents in dogs show that this mode

of administration does not improve blood flow to an ischemic organ.

Emu“? {DJ n
E

  

ll

Thulesius (44) demonstrated in the cat hindlimb that intravenously
infused vasodilator agents may have adverse effects on systemic
pressure and outflow from the occluded limb when given 2-3 minutes
after occlusion. Nicotinic acid was found to produce small and
inconsistant changes in systemic pressure and flow while azepetine
and isoxsuprine decreased systemic pressure and outflow from the
occluded limb. The decrease in outflow was due to both a decrease
in skin and muscle flow. However, isoxsuprine reduced muscle flow
proportionally more than skin flow. Coffman (6) and Lambert (25)
found that the collateral vasculature does not attain a steady state
in this short time.

De Bakey (8) questions the efficacy of systemically adminis-
tered vasodilator drugs. The apparent lack of a significant
increase in flow during intravenous administration of vasodilators
is thought to be a result of the decrease in perfusion pressure
'(aortic pressure) to the limb produced by generalized vasodilation
(15). Thus, even though the blood vessels may be dilated in the
limb following intravenous drug infusion, flow may not be altered
or may even be decreased because of the decrease in the driving
pressure. Local vasodilator drug administration is thought to
decrease limb resistance and may not affect perfusion pressure
thereby increasing limb blood flow.

Local administration of vasodilator agents has been performed
in various segments of the aorta and cognate artery of animals.
Thulesius (44) found that acute femoral artery occlusion resulted

in a feline muscle vascular bed that was non-reactive to the

12

vasodilator effects of exercise or intra-arterial (below the level
of occlusion) acetylcholine. However, the collateral vessels could
be dilated by intra-aortic acetylcholine.

Coffman (6) found that collateral blood flow increased and
vascular resistance decreased in the canine forelimb and hindlimb
on intra-aortic infusion of various vasodilator drugs after acute
ligation of the cognate artery. The increase in flow and decrease
in resistance was greater and more frequent in the hindlimb perhaps
due to the abundance of collateral vessels. However, Coffman did
not state where the intra-aortic infusions were administered. If
these infusions were given downstream to the subclavian artery
(the vessel which supplies the forelimb), the infusions would
have traversed the entire blood circuit before reaching the fore-
limb vascular bed and in reality he may have given intravenous
infusions.

Lambert (25) investigated the hemodynamic changes induced
by intra-arterial injections and short infusions of vasodilator
substances in the muscle circulation of the dog hindlimb after
occlusion of the femoral artery. He isolated the muscles of
the skinned left limb between ligatures to measure exclusively
muscle vascular bed blood flow. Ligation of the femoral artery
was performed one hour before the experiments. The intra-arterial
infusions of the vasodilatory drugs were made into a side branch
of the ipsilateral iliac artery proximal to the occlusion. This

infusion site would appear to most closely approximate the site

13

of administration in clinical usage. Lambert found that femoral
vein outflow from the occluded limb increased significantly after
local vasodilatory therapy. Collateral vessel resistance decreased
slightly and distal vascular resistance (distal pressure - venous
pressure/flow) decreased more than collateral vessel resistance
during vasodilator administration. However, it has been noted

(6) that his isolation of the musculature may have restricted
collateral flow. Also, the use of a skinned hindlimb may have
produced muscle blood flows which would differ from those in an
intact hindlimb.

The method of administration of a vasodilator agent may be
a variable factor which influences the magnitude of vascular res-
ponses to the agent. An injection may produce a high concentration
of the agent. Also, if the agent is short-acting it may produce
an effect which is ephemeral. An infusion of the same dose of the
agent may produce a lower concentration of the agent in the blood
and an effect which is longer in duration.

To reiterate, the purpose of this paper is to study two
phenomena in the dog forelimb after acute brachial artery occlusion:
first, to establish the level of resistance and to elucidate any
resistance changes which may occur in the collateral vessels
around the occlusion in the first few minutes after blockage;
and, second to compare the effects of systemically and locally
administered vasodilator compounds on forelimb muscle and skin

blood flow after acute occlusion of the brachial artery.

431.34g). .
13a; 8334_

14

The author has arbitrarily chosen Priscoline, papaverine and
Arlidin; one drug from each general class of peripheral vasodilators,
for use in this study. For a description of their pharmacological

action on the cardiovascular system see the appendix.

METHODS

Mongrel dogs (range 13-29 Kg) of both sexes were used. They
were anesthetized intravenously with sodium pentobarbital (30 mg/
K9) and ventilated with a mechanical respirator via an endotrachial
tube. They were anticoagulated with heparin (1 mg/Kg). The carotid
artery was cannulated for monitoring systemic pressure. The skin 1
of the medial aspect of the right forelimb was incised from the
elbow to the shoulder. Brachial artery pressure distal to the site

of eventual occlusion was monitored by means of a catheter placed

 

into a side branch of the brachial artery. Cephalic and brachial
venous pressures were monitored via catheters placed oppositely
into the median cubital vein on either side of a ligature (figure
2). The catheters were connected to four resistance wire trans-
ducers (Statham, Model P23Gb) which served as inputs into a

direct writing oscillograph (Sanborn, Boston, Mass.). Catheters
for intravenous and intrabrachial infusion of the drugs were placed
into the lesser saphenous vein and collateral ulnar artery respec-
tively. This artery was proximal to the site of eventual occlusion.
The brachial and cephalic veins were cannulated and their outflows
diverted into a reservoir. Blood from the reservoir was returned
to the jugular vein via a perfusion pump and catheter. It was
assumed that the brachial vein drained primarily muscle while the
cephalic vein primarily drained skin since the median cubital

vein, the main anastomotic channel between the skin and the muscle

15

 

 

l6

‘ A:
t—(— BRACHIAL ARTERY

— COLLATERAL ULNAR ARTERY

— CEPHALIC VEIN

 

MEDIAN CUBITAL VEIN E

\/
/ BRACHIAL VEIN

 

 

 

 

 

 

 

 

 

w: A, DRUG INFUSION
& ' TIE
“' ~. v PRESSURE
l PRESSURE
- PRESSURE

...,

 

 

 

 

 

 

 

Figure 2. Forelimb preparation

l7

circulation, was ligated (35). Outflows from the veins were
determined periodically with graduated cylinders and a stop watch.
Total limb flow was computed by adding the cephalic and brachial
outflows.

A complete brachial artery occlusion was accomplished by a
tight ligature placed around the vessel. Control flows were
taken prior to ligation, and serial flows, were taken at five
second intervals immediately upon ligation until 90 seconds after j
ligation. Ligation time was defined as time zero. The time factor I

and flows were placed into ten second groupings, that is, 0-9 seconds

 

after ligation, 10-19 seconds after ligation, etc. The average flow
and the average time in each group were computed.

The preparation was allowed to become stable for approximately
15 minutes after ligation before administration of a vasodilator
drug. The drugs were administered with an infusion pump (Harvard,
Model 901). Each drug was given at increasingly faster rates while
continuously monitoring the systemic and forelimb pressures. The
dose ranges for intravenous infusions were: Priscoline, 0.07-0.69
mg/Kg/min; papaverine, 0.08-0.82 mg/Kg/min; and Arlidin, 0.003-
0.03 mg/Kg/min. The dose for intrabrachial infusions were: Prisco-
line and papaverine, 0.002-0.02 mg/Kg/min; and Arlidin, 0.003-0.03
mg/Kg/min. Acetylcholine, a naturally occurring vasodilator, was
infused intravenously and intrabrachially from 0.05-1.00 mg/Kg/min
and 0.05-0.50 mg/Kg/min, respectively in order to compare its

effects with those of the other drugs. The agents were given in

18

random sequence. However, the intrabrachial infusions were always
given first to prevent complicating changes in systemic pressure
which might be elicited by intravenous infusions. Fifteen second
flows were taken at appropriate times before, during and after
infusion. At each drug level and during control periods the
pressures were allowed to stabilize before the flow was determined.

The catheters which were inserted into the veins were open to

-" m’?_.fl' TLH‘IHQI

the atmosphere and represented fixed resistances which did not
vary during the experiments. Hence, the individual total resis-

tance for each forelimb was calculated by dividing the systemic

 

pressure by the total flow. Collateral resistance was calculated
according to the formula; systemic pressure - distal brachial

artery pressure/total flow. Distal skin and muscle vessel resis-
tance values were computed according to the formula; distal brachial
artery pressure/appropriate flow. The student t test (46) was used

as a measure of significance of the results.

RESULTS

Table 2 illustrates the average effects of acute ligation on
the forelimb vasculature in 15 mongrel dogs. Within an average
of 15 seconds after ligation total venous outflow fell 61% below

control value from a preocclusion average value of 7.1 ml/S Sec

—"."-"‘v‘il In“ *1

to an average value of 2.8 m1/5 sec. Total forelimb venous out-
flow began to increase and at 74 seconds after ligation outflow

had risen to an average value of 3.2 ml/5 sec (55% below the

 

 

control value). An increase in total venous outflow occurred in l
12 animals while in 3 animals flow did not change. From 74
seconds to 15 minutes after occlusion, forelimb outflow did not
change. Approximately 15 minutes after ligation average venous
outflow was at a value 56% below the preocclusion levels.

A typical brachial artery pressure tracing as monitored
below the level of occlusion is shown in figure 3. In 15 experi-
ments distal brachial artery pressure fell to an average of 25
mm Hg 15 seconds after occlusion. Distal brachial artery pressure
gradually rose to 30 mm Hg 74 seconds after ligation. Distal
brachial artery pressure continued to rise and at approximately
15 minutes after ligation it was at 41 mm Hg. Systemic arterial

pressure remained unchanged throughout the entire period.

19

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15 MINUTES
POST OCCLUSION

*— TEN SECONDS

Typical brachial artery pressure tracing

before and

Figure 3.

l

diately after brachia

1mme

artery occlusion.

22

Average collateral resistance in the dog forelimb decreased
significantly from 41 mm Hg/ml/5 sec at 15 seconds after ligation
to 34 mm Hg/ml/S sec at 74 seconds after ligation to 27 mm Hg/ml/
5 sec at approximately 15 min after occlusion.

The changes which occurred in the other forelimb resistances

after acute arterial occlusion are noteworthy. Total forelimb

1 “I

resistance rose from an average control value of 20 mm Hg/ml/5 sec
to 51 mm Hg/ml/5 sec at 15 seconds after occlusion. During this
time distal brachial and cephalic resistance fell from control

values of 38 and 41 mm Hg/ml/5 sec respectively to 24 and 21 mm Hg/

 

ml/5 sec respectively. From 15 to 74 seconds total forelimb resis-
tance fell from 51 to 44 mm Hg/ml/5 sec while distal brachial and
cephalic resistances did not change. From 74 seconds to approxi-
mately 15 minutes after ligation, total forelimb resistance was
not altered. During this period distal brachial and cephalic
resistance both rose from 23 mm Hg/ml/S sec to 31 and 30 mm Hg/
ml/5 sec respectively.

Figure 4 illustrates the average changes observed with a
continuous infusion of intravenous Priscoline on total, brachial
and cephalic outflows and aortic and distal brachial artery
pressure. No significant changes in total or cephalic outflow
occurred. However, there was a significant increase in brachial
vein outflow from a control value of 15.1 ml/min to a value of
18.7 ml/min at an infusion rate of 12.8 mg/min. Aortic pressure

and distal brachial artery pressure did not change significantly.

FLOW ML IMIN

PRESSURE ' mm .Hg

23

IO

N

TOTAL OUTFLOW

T fi

204

 

-
v
v

a): P<.Ol

30‘\ ///T'

)k

BgACHIAL OUTFLOL”//,—.

 

 

L M ;— t
'0‘ CEPHALIC OUTFLOW
I501-
AORTIC

 

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;: BRACHIAL ARTERY

2K)..

:25 5 i 5 ‘ 5 i 5 ‘i
O 2.0 4.0 5.0 8.0 0.0 I20 I40

INFUSION RATE MGM / MIN

Figure 4. Average effects of a continuous intravenous infusion

of Priscoline

um-fll'

 

 

24

However, aortic pressure rose in 7 of 10 experiments. Intra-
venously administered Priscoline did not significantly alter
average forelimb total, collateral, distal brachial or distal
cephalic resistance from the control values at the highest
infusion rate. Although distal brachial resistance did not
change significantly it fell in 7 of 10 experiments. Hence,
the rise in brachial outflow was associated with a rise in
perfusion pressure or a decrease in brachial resistance or
both.

Figure 5 shows the average effects of an intrabrachial
infusion of Priscoline on outflows and pressures. Total flow
decreased significantly from a control value of 39.4 ml/min to
35.8 ml/min at the highest rate of infusion. The decrease in
total outflow was due to a decrease in cephalic venous outflow.
Brachial outflow and aortic and distal brachial artery pressure
did not change significantly. However, aortic pressure rose in
7 of 10 experiments. Calculated average forelimb total resis-
tance rose from a control value of 3.6 mm Hg/ml/min to 4.2
mm Hg/ml/min at the highest infusion rate. Collateral and
brachial resistances did not change significantly during intra-
brachial Priscoline infusion. Distal cephalic resistance rose
significantly from an average control value of 2.8 mm Hg/ml/min
to 4.5 mm Hg/ml/min at the highest infusion rate.

The effect of a continuous infusion of intravenous papaverine

in nine mongrel dogs is illustrated in figure 6. Intravenous

25

 

 

 

 

 

 

 

 

 

 

 

 

 

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+ P I .OZ-.O5
40 TOTAL OUTFLow ,
\fi 4' g + i
E
E aoI.
3’ BRfiCl-IIAL OUTFLOW
V 4 3
g 20"
CEPHALIC OUTFLOW
KJJL
“if
a? AORTIC a
E _
E '25?‘ 4 t '
... it
g ' BRACHIAL ARTERY
(I) 50-11- 4//
m k -
E- f
25 : e : a z c
o 0.04 0.09 0.12 0.10 0.20 024

INFUSION RATE MGM / MIN

Figure 5. Average effects of a continuous intrabrachial infusion of
Priscoline

26

 

 

 

 

 

 

 
 

 

 

N - 9
“L ak P< .0:
g TOTAL 0um.0w . A if
3 ”(AL 3 t: . ‘
x |
i
’ I
3 2°” ERACHIAL OUTFLOW I
l ‘~;— 4' ‘f ‘3
IP"— “-1r1;:;r-—- 2: Ti:
I0-L CEPI-IALIC OUTFLOW
1509 .
:8 4 AORTIC
E IZB‘
é BRACHIAL ARTERY
28 i i V i 5 5 J.
, 0 so 0.0 so 120 15.0 no

INFUSION RATE MGM IMIN

Figure 6. Average effects of a continuous intravenous infusion of papaverine

 

27

papaverine did not alter total, brachial or cephalic outflow.
However, aortic pressure fell significantly from a control
value of 134 mm Hg to 107 mm Hg at the highest infusion rate.
Distal brachial artery pressure also fell from an average control
value of 60 mm Hg to 37 mm Hg at the highest infusion rate and
total forelimb resistance decreased from a control value of
5.8 mm Hg/ml/min to 4.3 mm Hg/ml/min. Average forelimb collateral
resistance did not change significantly during intravenous papav-
erine infusion. Distal brachial resistance fell from an average
control value of 5.0 mm Hg/ml/min to 2.7 mm Hg/ml/min at the
highest infusion rate and distal cephalic resistance decreased
from an average control value of 6.6 mm Hg/ml/min to 3.6 mm Hg/
ml/min.

Intrabrachial papaverine's effect in 10 mongrel dogs is
illustrated in figure 7. Total flow increased significantly
from a control value of 37.6 ml/min to 43.7 ml/min at the highest
infusion rate. Brachial venous outflow increased from 19.0 ml/min
during the control period to 23.9 ml/min at the highest infusion
rate. Cephalic venous outflow and aortic and distal brachial
artery pressure were not significantly altered. Intrabrachial
infusion of papaverine did not significantly alter average
forelimb total, collateral, brachial or cephalic limb resistance
from the control values. In 7 of 11 experiments the increase in
muscle blood flow was associated with a decrease in muscle vascu-

lar resistance while in one of the experiments the increase in

£28

I!
11

 

FLOW

 

 

 

 

 

 

 

 

50-- 9k P<.OI
g,
TOTAL OUTFLow
40*-
E 1.— ; L
2
\
3’ 30..
BRACHIAL OUTFLOW 9“
204) : D
; A/ ‘
CEPHALIC OUTFLow
'0 db
1501-
g AORTIC
E a : s
5125 fi-

   
  

BRACHIAL ARTERY

g

A
'

 

 

25 - + + e I 1 1
o 0.05 0.10 0.15 0.25 0.30 0.35
INFUSION RATE MGM/MIN

Figure 7.

Average effects of a continuous

intrabrachial infusion of papaverine

 

29

flow was associated with a proportionally greater rise in perfusion
pressure. In the remaining three experiments muscle blood flow was
not altered but muscle resistance increased in one experiment con—
comintantly with a rise in perfusion pressure, while in the other
two experiments muscle vascular resistance did not change.

The effect of a systemic infusion of Arlidin on forelimb
outflow and aortic pressure in 10 mongrel dogs is illustrated in
figure 8. Intravenous Arlidin did not significantly alter total,
brachial or cephalic outflow at any infusion rate. Aortic pressure
was significantly decreased from a control value of 119 mm Hg to
114 mm Hg at an infusion rate of 0.14 mg/min. Aortic pressure
progressively fell over the next two infusion rates. The effects
of intravenously administered Arlidin were much like those of
intravenous papaverine. Distal brachial artery pressure fell
significantly from a control value of 38 mm Hg to 29 mm Hg at
the highest infusion rate. Average forelimb total, collateral,
brachial and cephalic resistances were not altered from control
values at the highest infusion rate of intravenously administered
Arlidin. However, total, brachial and cephalic resistances fell
in 6 of 11 experiments.

Figure 9 illustrates the average effects of an intrabrachial
Arlidin infusion on forelimb flows and pressures in 10 animals.
Total outflow increased from a control value of 35.5 ml/min to
43.5 ml/min at an infusion rate of 0.56 mg/min. The increase in

total flow was due primarily to an increase in brachial venous

, .....JI

3(3

 

 

 

 

 

 

N=|O
an P<.OI
504-
TOTAL OUTFLOW
” 4 T : 4
E
2
\
1 30-11»
g ’{BRACHIAL OUTFLOW
-“' 201:; v; L F: T:
XCEPHALIC OUTFLOW
~10¢-
12511- AORTIC
I
5‘ ale
1: ICK).. at
m
o:
a
on
v:
1.1.1
2 50*.
BRACHIAL ARTERY
1L—\ 3*
25 . :

 

0 0'10 020 0730 0740 0.30 0.150
iNFUSION RATE MGM IMIN

Figure 8. Average effects of a continuous intravenous infusion of Arlidin

 

 

 

3 I

N'IO 9k P< .OI

 

 

 

 

 

soil .1. P-.02-.05
TOTAL OUTFLOW j
40$ A ;
2
I
\
..1
3 304A
BRACHIAL OUTFLOW +
3 1" f a
3
IL 20»
CEPHALIC OUTFLOW
IO

 

 

 

 

 

AORTIC ,
125 +
4.

e i *
E 001)-
; BRACHIAL ARTERY
m 50
u
c
o.

25 1 1r : : : i

0 0.I0 0.20 0.30 0.40 0.50 0.60

INFUSION RATE MGM/MIN

Figure 9. Average effects of a continuous intrabrachial infusion of Arlidin

 

32

outflow which rose dramatically in 7 of 10 experiments at 0.11
mg/min and 0.28 mg/min while at 0.56 mg/min brachial outflow
increased in 9 of 10 experiments. Cephalic venous outflow was

not significantly altered at any infusion rate. As with intra-
venously administered Arlidin, systemic pressure fell significantly
over the higher infusion rates. Distal brachial artery pressure
also decreased from a control value of 49 mm Hg to 33 mm Hg at the
highest infusion rate. Total forelimb resistance decreased from
an average control value of 4.1 mm Hg/ml/min to 2.9 mm Hg/ml/min
at the highest infusion rate. Average forelimb collateral resis-
tance did not change significantly during intrabrachial Arlidin
infusion. Average distal cephalic resistance decreased from an
average control value of 3.9 mm Hg/ml/min to 2.6 mm Hg/ml/min at
the highest infusion rate. Average distal muscle resistance

' decreased from a control value of 3.0 mm Hg/ml/min to 1.6 mm Hg/
ml/min at the highest infusion rate.

Figure 10 illustrates the average effects of an intravenous
infusion of acetylcholine on total, brachial and cephalic vein
outflow as well as aortic pressure and distal brachial artery
pressure. 'There were no significant changes in any of the par-
ameters measured at any infusion rate.

The average effects of an intrabrachial infusion of acetyl-
choline are illustrated in figure 11. Total flow increased
significantly from a control value of 43.1 ml/min to 46.7 ml/min

at an infusion rate of 2 ug/min. Total flow continued to increase

33

 

 

 

 

N = IO
TOTAL OUTFLOW
14CJ1P A__
V_ 4
E
2
3 304.
2
g gCEPHALIC OUTFLOW
1‘ 20 -- a = e i _.
(RN—r ‘ 3
(J
BRACHIAL OUTFLOW
IO‘b
15C)!-
:1?
AORTIC
E 1254 s . 4. A.

 

PRESSURE
01
o

 

BRACHIAL ARTERY

A
v f

 

225 I I, I F *4
C) 5 1() I5 2C) 225
INFUSION RATE AGM / MIN
Figure 10. Average effects of a continuous intravenous infusion of

acetylcholine

 

 

34
Ngll itP<.0|

 
   

 

 

 

 

 

 

 

+ P = 02-054,
504)
1 TOTAL OUTFLOW
2 GP
:40
\
..J
2
k
3 30 ,. BRACHIAL OUJFLOW A
o i“? ‘
.1
LL
JP_____c’///I.TT-”’Tfl—fl—T———flfl—r ___£
204* a—g 4
CEPHALIC OUTFLOW
[0.11.
'25" AORTIC
. g ‘h—b-k 4' £
a
e
100 1"
DJ
E i;
3
u 50 «-
E BRACHIAL ARTERY
1h“ 3 _ .1.
25 : 4 1 1 1
I) 2. 4- 61 . 8 H3

INFUSION RATE AGM/MIN

Figure 11. Average effects of a continuous intrabrachial infusion of
acetylcholine

 

35

over the next three infusion rates. The increase in total outflow
was due to a rise in brachial vein outflow which rose from a control
value of 22.7 ml/min to 26.3 ml/min at an infusion rate of2 pg/min.
Brachial vein outflow also continued to rise over the next three
infusion rates. Cephalic vein outflow and systemic pressure were
not significantly altered at any infusion rate. However, cephalic
vein outflow increased in 7 of 11 experiments. Distal brachial
artery pressure decreased from a control level of 37 mm Hg to

33 mm Hg at the highest infusion rate. Calculated total forelimb
resistance decreased from a control value of 3.1 mm Hg/ml/min to
2.5 mm Hg/ml/min at the highest infusion rate. Average collateral
vessel resistance was not altered at any infusion rate. Average
distal brachial resistance fell from a control value of 1.9 mm Hg/
ml/min to 1.4 mm Hg/ml/min at the highest infusion rate. Average
distal cephalic resistance fell from 2.8 mm Hg/ml/min to 2.2 mm Hg/
ml/min at the highest infusion rate.

Table 3 illustrates the significant effects of intravenously
and intrabrachially administered vasodilators on brachial, cephalic
and total outflows following acute brachial arterial occlusion.

The effects are expressed as per cent change from control at the
highest infusion rate. The effects are also compared with the
effects of acetylcholine, a naturally occurring vasodilator.

The highest infusion rate of Priscoline increased muscle flow
24% above control but had no effect on skin and total flow.

Intravenous papaverine, Arlidin and acetylcholine did not

36
TABLE 3

Effect of vasodilators on brachial, cephalic, and total flows in
the forelimb after acute arterial occlusion

 

 

Intravenous Intrabrachial
23.59:: 513.1111.
Priscoline +24% ---- ---- ---- +20% +9%
Papaverine ---- ---- ---- +26% ---- +16%
Arlidin ---- ---- ---- +35% ---- +22%

Acetylcholine ---- ---- ---- +31% ---- +17%

 

 

37

significantly alter venous outflows. The highest dose of Pris-
coline did not affect brachial flow but cephalic flow decreased 20%
below control and total flow was 9% below control. Local infusions
of papaverine increased brachial flow 26% above control, did not
significantly alter skin flow, and increased total flow by 16%.
Intrabrachially administered Arlidin increased brachial venous
outflow to a value of 35% above the control venous outflow. The
increase in brachial venous outflow produced a resultant increase
in total flow which was 22% above control. Cephalic venous outflow
was not significantly altered at the highest infusion rate. By
comparison, a local infusion of acetylcholine increased brachial
flow 31% above the pre-infusion levels, did not alter cephalic

flow and increased total flow 17% above control.

 

DISCUSSION

Blood flow through a vascular bed is determined by the
resistance to flow through the bed and the pressure gradient
for flow across the bed. A decrease in resistance with no
change in the pressure gradient will increase blood flow
whereas an increase in resistance with no change in the pres-
sure gradient will decrease blood flow. An increase in the ‘
pressure gradient with no change in resistance will increase
blood flow and vice versa. Resistance can change because of
alterations in 1) blood viscosity, 2) vessel length, or 3)
vessel radius. Vessel radius may change actively or passively.
An active change in vessel radius is due to any alteration in
the contractile state of the vascular smooth muscle. An example
of the latter is the change in vascular resistance produced by
a thrombus.

After ligation of the brachial artery blood flow to the
forelimb is supplied via the collateral circulation. Under
this circumstance, forelimb flow is not only influenced by
changes in aortic pressure and changes in vascular resistance
downstream to the point of occlusion but also by changes in
resistance in the collateral vessels. In the present studies
total forelimb resistance was composed of a collateral resis-
tance in series with each of two distal parallel resistances
(skin and muscle). The skin and muscle beds may contain both
collateral and distal resistances. Since the collateral supply

38

39

is not specific to either of these beds, the amount of collateral
blood flow that perfuses each bed will depend on the collateral
and distal resistances. The maximum flow increase would be ob-
tained if both resistances were reduced. The results of the

present study will be discussed in light of the above format.

Collateral Circulation and Ligation

During the first 15 seconds after acute brachial artery
occlusion distal brachial artery pressure and total blood flow
decrease. Resistance calculations utilizing the venous outflow
during the period may not be reliable as sizable alterations in
the arterial inflow to venous outflow ratio of the forelimb
probably occur. Acute ligation of the brachial artery trans-
iently produces an arterial inflow which is probably less than
the venous outflow due to the abrupt increase in resistance in
the major artery occasioned by the ligature. The reduced
arterial inflow also would tend to decrease volume and hence
transmural pressure in the distal vessels. A decrease in trans-
mural pressure passively constricts the vessels such that during
this time emptying of the vascular tree occurs. Subsequently,
the situation may be reversed and arterial inflow may be greater
than venous outflow as the collaterals open and supply blood to
the distal vascular tree. Fifteen seconds post occlusion it is
assumed that the arterial inflow closely approximated the venous

outflow.

 

40

In this study forelimb collateral resistance decreased during
the period of 15 to 74 seconds after acute arterial occlusion.
However, it must be noted that there were small differences in
individual outflows during this time period and the possibility
of error in quantitating blood flow exists due to the method and
time alloted for collecting each flow. With this in mind, the
apparent decrease in collateral resistance observed in the dog
forelimb agrees with the findings of others in the dog and cat
hindlimb (40)(44). The causative agent for the decrease in
collateral resistance is unknown. There is no reason to suspect
a decrease in blood viscosity or vessel length or passive changes
in vessel radius. The decrease in intraluminal pressure observed
during this time would tend to passively decrease vessel radius
and raise collateral vessel resistance. An active change in
vessel radius is most likely the causative factor for the decrease
in collateral vessel resistance observed immediately after acute
arterial occlusion. Remote controlling mechanisms such as
sympathicoadrenal inhibition do not participate as there is no
stimulus since systemic pressure was not altered. It has also
been demonstrated that elimination of extrinsic neural influences
does not alter the collateral vessel response to ligation (40).
The dilation appears to be a locally produced and regulated
phenomenon. The decrease in intraluminal pressure may act to
elicit a reverse Bayliss response. The possibility that an

ascending cell to cell propagation of electrical activity

"A

 

41

may occur, has been hypothesized(12)(44). Also, the participation
of locally produced vasoactive chemical agents such as oxygen,
carbon dioxide and the hydrogen ion has been suggested (40).
Coffman (6) and Rosenthal and Guyton (40) have demonstrated that
the collateral vessel resistance can be affected by exercise and
hypotension, respectively. These conditions may result at least
in part from an alteration in the concentration of chemical sub-
stances (18). At this time no one mechanism has been demonstrated
to be solely responsible for the decrease in collateral vessel
resistance seen immediately after acute arterial occlusion.
However, the diminution in flow produced by ligation would allow
for the gradual alteration in concentration of chemical substances
in the blood and in the tissues surrounding the collateral vessels
such that these substances may play a significant role in deter-
mining the progressive decrease in collateral vessel resistance
seen immediately after ligation.

In the first 15 seconds after occlusion total resistance
rose while distal brachial and cephalic resistance fell. The
rise in total resistance was the result of a passive constriction
of the brachial artery due to the occlusion. The fall in brachial
and cephalic resistance was the algebraic sum of opposing effects.
The decrease in total blood flow through the limb produced by the
ligation would tend to decrease transmural pressure, an effect
which would passively constrict the vessel. 0n the other hand,

the altered concentration of vasoactive chemicals due to the

 

42

decreased blood flow would tend to actively increase vessel
radius thus lowering the resistance to flow.

Total forelimb resistance continued to fall from 15-74
seconds after occlusion. The fall in total resistance was due
to the decrease in collateral vessel resistance since brachial
and cephalic resistances were unaltered.

From 74 seconds to approximately 15 minutes after ligation
total resistance was not significantly altered. However, during

this period a further decrease in collateral resistance was

 

observed. The mechanism for this decrease in resistance was
probably the same one which produced the initial decrease in
collateral vessel resistance. Distal brachial and cephalic
resistance rose during this time period. The total flow was
unchanged. The physiological mechanism or mechanisms which

are acting to produce these changes are unknown.

Vasodilator Drug Infusion

 

The salient findings of the present study with regard to
vasodilator therapy are: 1) during intravenous infusion none of
the agents tested produced an increase in total outflow from the
dog forelimb after occlusion of the brachial artery. Furthermore,
except for Priscoline, none of the agents affected flow through
skin or muscle. Intravenous Priscoline produced small but regular
increases in muscle vein outflow; 2) during intrabrachial infusion

of papaverine, Arlidin and acetylcholine, total outflow increased

43

due to an increase in muscle vein outflow while skin vein outflow
did not change. Intrabrachial infusion of Priscoline produced a
decrease in total outflow due to a decrease in skin vein outflow
while muscle vein outflow did not change; and 3) collateral resis-
tance was not affected by an agent regardless of the route of
administration. Hence, the changes in limb outflow were the
result of changes in resistance down stream to the collaterals or
changes in the driving pressure.

After acute brachial artery occlusion forelimb flow is

supplied exclusively by the collateral vessels and there is a

 

marked decrease in forelimb blood flow. Generally, intraven-
ously administered vasodilator agents tested did not affect
this reduced blood flow because they did not lower forelimb
resistances or if they lowered forelimb resistances they
decreased systemic pressure proportionally. An exception to
this is the finding that intravenously administered Priscoline
produced small but regular increases in muscle vein outflow
while other forelimb blood flows, systemic pressure and forelimb
resistances were not regularly affected. In individual experi-
ments the rise in flow was sometimes associated either with a
rise in perfusion pressure or a fall in muscle resistance or
both.

Intravenous infusion of papaverine produced a fall in systemic
pressure which was proportional to the fall in forelimb resistance.

Consequently, there was no change in forelimb blood flow. The fall

 

44

in systemic pressure tended to passively decrease vessel caliber
by decreasing transmural pressure. However, since a decrease in
forelimb resistance was observed the active dilation produced by
the drug may have been greater than the passive constriction due
to the fall in transmural pressure occasioned by the fall in
systemic pressure.

Intravenous infusion of Arlidin did not significantly change
forelimb resistance or blood flow while it decreased systemic
pressure. The finding that total forelimb resistance was not
altered concomitantly with a decrease in systemic pressure might
be explained in the following manner. The active dilation pro-
duced by the drug may have been balanced by a passive constric-
tion produced by the fall in transmural pressure. This hypothesis
is supported by the finding that total, brachial and cephalic
resistance fell in six of eleven experiments. The decrease in
forelimb resistances combined with a decrease in systemic pressure
produced no net change in forelimb outflow.

Intrabrachial infusions of vasodilator drugs affected forelimb

blood flows by altering distal skin and muscle resistances]. Local

1

 

All vasodilator agents were infused in an isotonic saline medium
Consequently, the role of a reduction in blood viscosity in the
resistance changes observed must be considered. The greatest
volume infusion rate given was 2 ml/min. The average forelimb
blood flow during the infusion was 50 ml/min. Molnar et. a1. (36)
demonstrated that infusions of isotonic saline of 6.4 fiT7mTfi into

a constant arterial inflow of 100 ml/min did not have a significant
effect on total forelimb resistance. This indirect evidence sug-
gests that the effects of viscosity on forelimb resistance during
vasodilator infusion were minimal if any.

 

45

administration of papaverine, Arlidin and acetylcholine produced
moderate but regular increases in total and muscle blood flow
presumably by actively dilating muscle vessels since systemic
pressure was not increased. These agents did not affect skin
blood flow. Intrabrachially administered Priscoline decreased
total and skin blood flow by increasing the skin vascular r!
resistance, again probably an active effect on vessel caliber.
Muscle blood flow and resistance as well as systemic pressure

were not altered. Benfey and Varma (5) have reported that 0.5

 

mg/Kg intravenous injections of Priscoline increase systemic

11T- -

pressure by increasing cardiac output and actively constricting
the peripheral vasculature. This study in which approximately
0.02 mg/Kg was given at the highest infusion rate demonstrates
that a local infusion of Priscoline constricts the skin vascular
bed while not affecting the forelimb skeletal muscle vascular
bed.

Local infusion of papaverine increased total blood flow
primarily by increasing muscle blood flow; skin blood flow,
muscle and skin resistances and systemic pressure were not
altered. In 7 of 11 experiments the increase in muscle blood
flow was associated with a decrease in muscle vascular resis-
tance while in one of the experiments the increase in flow was
associated with a rise in resistance but there was a propor-
tionally greater rise in perfusion pressure. In the remaining

three experiments muscle blood flow was not altered but muscle

46

resistance increased in one experiment concomitantly with a rise
in perfusion pressure, while in the other two muscle vascular beds
resistance did not change. Hence, the rise in muscle blood flow
was due to a decrease in muscle resistance or an increase in
perfusion pressure or both.

Intrabrachial infusion of Arlidin increased total blood flow by
increasing muscle blood flow without significantly affecting skin
blood flow. Systemic pressure, total, brachial and cephalic resis-
tance decreased. The decrease in total and muscle resistance was
proportionally greater than the fall in systemic pressure as total
and muscle blood flow increased. The fall in skin vascular resis-
tance was in proportion to the decrease in systemic pressure as
skin blood flow was unaltered. The fall in skin and muscle vascular
resistance indicates that the active dilation produced by the agent
in these beds must have been greater than any passive effects pro-
duced by a fall in systemic pressure due to the systemic effects
of this drug.

Intravenously infused acetylcholine did not affect any of
the parameters measured. The lack of action of acetylcholine is
probably due to its rapid destruction by blood cholinesterases
(l6). Intrabrachially infused acetylcholine increased total and
brachial vein outflows. Cephalic vein outflow and systemic

pressure were not significantly altered. However, cephalic

 

47

vein outflow rose in 7 of 11 experiments. Brachial artery
pressure decreased. Total forelimb and distal brachial and
cephalic resistances decreased. Collateral resistance was
unaltered. Intrabrachially administered acetylcholine actively
dilated the distal brachial and cephalic vasculature while not

affecting the collateral vasculature.

Jun-m A...“

Except for a local infusion of Arlidin, none of the agents
tested increased forelimb blood flow above the control blood
flow values as much as locally infused acetylcholine.

Collateral resistance was not altered significantly by any 1

 

of the agents during either route of administration. This might
be explained by l) maximal dilation of collateral vessels, 2)
failure of the drug to reach the entire collateral circulation,
3) insensitivity of-the collateral blood vessels to the dilators.
The absence of a decrease in collateral vessel resistance during
intravenous papaverine infusion in spite of significant reduc-

- tions of all other forelimb resistances is especially noteworthy.
It is possible that the reduction in the distal artery pressure
decreased collateral vessel transmural pressure significantly.

A fall in transmural pressure would produce a passive decrease

in radius and an increase in resistance. This passive effect

on vessel radius may have balanced any active dilation produced
by the drug such that there was no net change in collateral

vessel resistance. The lack of a change in collateral vessel

48

resistance during intrabrachial administration of vasodilator
drugs may be due to the site at which the agents were given.
It has been demonstrated in other studies (6)(44) that the
collateral vessels of the forelimb and hindlimb vascular beds

are capable of resistance decreases when the vasodilator drugs

 

 

are administered intra-aortically. In our forelimb study the FT
local infusion of the agents was made downstream to the aorta i
but upstream to the ligature. The drugs may have traversed a

relatively small number of the collateral vessels and produced

no net change in collateral resistance while significantly is

affecting the distal vascular beds. Due to the series nature
of the collateral vessels in relation to each of the distal
vascular beds, it would be beneficial to decrease collateral
vessel resistance in order to produce a more efficient therapy.
It is worthy to note that excessive amounts of the vaso-
dilator drugs during either route of administration were not
necessary in order to elicit changes in pressure and flow.
The approximate total amount of each of the vasodilator drugs
administered per kilogram of dog at the highest infusion rate
(Priscoline, 1.3 mg/Kg; papaverine, 1.5 mg/Kg/ and Arlidin,
0.07 mg/Kg) closely paralleled the recommended (16) doses for
human intravenous infusion (Priscoline, 2.9 mg/Kg; papaverine,

1.4 mg/Kg; and Arlidin, 0.07 mg/Kg).

SUMMARY AND CONCLUSIONS

The purpose of this study was to determine the changes in
the resistance to blood flow through collateral vessels in the
canine forelimb immediately after acute arterial ligation and
to establish the effects of vasodilator drug administration by
two routes on blood flow through the collateral vessels. This I .
was accomplished in the following manner. The brachial artery
was acutely ligated while continuously monitoring systemic

arterial blood pressure and brachial artery pressure distal to

 

the occlusion site; five second serial blood flows were collected
from the cannulated brachial and cephalic veins in graduated
cylinders. Vasodilator agents (papaverine, Priscoline, Arlidin,
acetylcholine) were then given intrabrachially and intravenously
in random sequence at progressively faster infusion rates.
Collateral resistance was calculated by the formula systemic
pressure - distal brachial artery pressure/total flow. Distal
resistances in skin and muscle were calculated by dividing

the distal brachial artery pressure by the appropriate flow.

The effects of acute ligation of the brachial artery were
an immediate decrease in distal brachial and cephalic resis-
tances as well as a decrease in collateral vessel resistance
from 15 to 74 seconds after occlusion. The salient findings

with regard to vasodilator drug infusion were: 1) an increase

49

50

in muscle vein outflow during intravenous infusion of Priscoline;
but no effect on forelimb flows with other drugs tested, 2) an
increase in muscle vein outflow during infusion of papaverine,
acetylcholine and Arlidin and a fall in skin blood flow during
intrabrachial Priscoline infusion, 3) a fall in distal resistances
without changes in collateral resistance during infusion of the
agents.

This study demonstrates that collateral vessel resistance
decreases from 15 to 74 seconds after ligation. It also shows
that the route of administration is important when vasodilator
drugs are employed to increase canine forelimb collateral blood

flow around an acutely ligated cognate artery.

 

10.
11.

12.

BIBLIOGRAPHY

Ahlquist, P.P., R.A. Huggins and R.A. Woodbury. The Pharma-
cology of Priscol. J. Pharmac. Exptl. Therap. 89:271-288,
1947.

Barcroft, H., gt, 31, Blood Circulation of of Muscle in
Humans in Indirect Warming and Cooling. Pflugers Arch.
261:199, 1955.

Barcroft, H. Circulation in Skeletal Muscle. Handbook of
Physiology (Circulation) Baltimore, Waverly Press. II:1353,
1963.

Bard, P. Medical Physiology. St. Louis, C.V. Mosby Co.,
1961, p. 240.

Benfey, B. and D.R. Varma. 0n the Hypertensive Action of
Tolazoline and Hydergine. Canadian J. of Biochem. and
Physiol. 41:941, 1963.

Coffman, J.D. Peripheral Collateral Blood Flow and Vascular
Reactivity in the Dog. J. Clin. Invest. 45:923, 1966.

Daugherty, R.M., Jr., et. 91, Comparison of iv and ia Infus-
ion of Vasoactive AgenTE'on Dog Forelimb Blood Flow. Am. J.
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APPENDIX

APPENDIX

Cardiovascular Pharmacology_of Drugs used in this Study
Tolazoline (Priscoline, Priscol) hydrochloride (CIBA), a
2-benzyl 2—imidazole hydrochloride was first described in 1939
(19). Benfey and Varma (5) reported that intravenous injections
of low doses (0.5 mg/Kg) of Priscoline into the dog increased
myocardial contractile activity and mean arterial blood pressure
in two of four animals tested. In eight dogs pretreated with
reserpine, 0.5 mg/Kg intravenous injections of Priscoline, in-
creased myocardial contractile activity and mean arterial blood
pressure in every animal tested. However, in animals pretreated
with reserpine and phenoxybenzamine the same injections of Pris-
coline did not change myocardial contractile activity or mean

arterial blood pressure. The authors

/I concluded that Priscoline "is a partial
HN r
sympathomimetic agonist with a low
CH2 efficacy and a high affinity of vaso-

constrictor receptors.”
Ahlquist (1) in 1946 found when 1-10
1 “CI mg were injected intravenously into the
dog that systemic pressure had a tendency to rise although no
statistically significant changes in systemic pressure occurred.
He attributed the apparent pressure response to an increase in

cardiac output which he measured by the dye dilution method.
55

 

DPS-“run

56

Ten gm of Priscoline frequently more than doubled cardiac output.
In a perfused dog heart preparation, Ahlquist found that one mg
of Priscoline when injected locally produced a sympathomimetic
effect which acted synegistically when combined with a sub—minimal
dose of epinephrine. Other investigators have confirmed the.
sympathomimetic effect of Priscoline (9)(31). Ahlquist has also
demonstrated that an intravenous or intra-arterial injection of
1.00-10 mg of Priscoline increased flow in the skinned and intact
dog hindlimb. Many investigators attribute Priscoline's vascular
dilating capacity to adrenergic blocking activity and vascular
smooth muscle relaxing properties (20)(31). The vasodilation
produced by Priscoline appears to be more marked in the skin
vascular bed than in the muscle vascular bed (9). Braun placed
the site of action on the arteries, arterioles and arteriovenous
anastomoses. If Priscoline does increase arteriovenous anastomose
flow greatly its efficacy as a useful vasodilator may be dimini-
shed. An increase in flow due mainly to an increase in
non-nutritional or arteriovenous shunt flow would not increase
the amount of nutrient reaching the cells. Tolazoline is excreted
into the urine practically unchanged (43).

Papaverine, (Eli Lilly and Company), an isoquinoline alkal-
oid of opium was described by Merck (34) in 1848. Pal (38) in

1913 cited the smooth muscle relaxing properties of papaverine.

 

 

57

He stated that the drug relaxed smooth muscle without paralyzing

it. Macht (32) studied the cardiovascular effects of an intra-

venous injection of papaverine on the intact dog heart. Using a
cardiac plethysmograph he found

that small doses of the drug pro-
11 CO

duced a decrease in heart rate.
II CD N
Macht also stated that an increase

3

in the strength of contraction and

2 the cardiac output of the heart
were observed. Cutting the vagii,
blocking with atropine and destroying
CH3 the stellate ganglion did not diminish
OCH3 the response of the heart to the drug.

Thus, papaverine does not appear to act on extrinsic mechanisms
during cardiac regulation. Furthermore, Macht noted a decrease in
systemic pressure in the intact dog after an intravenous papaverine
injection. Resultant studies showed that intravenously injected
papaverine produced a marked vasodilation in the peripheral,
splanchnic and coronary vascular beds. Other investigators have
noted decreases in systemic pressure with intravenously adminis-
tered papaverine (20). Dragendorff (10) has found that papaverine
is unchanged in the body and is chiefly excreted in the urine,

bile and partly through the small intestine.

 

 

58

Nylidrin (Arlidin) hydrochloride (U.S. Vitamin and Pharma-
ceutical Corporation), a pheny1-2-buty1 norsuprifen hydrochloride
was first produced by Kulz and Schneider in 1950 (24). The drug

is chemically related to the epinephrine, ephedrine type of

3 compound. Freedman (13) observed
HO CH
<:::::>P- that a 0.1 mg/Kg systemic (sub-
H3C-(HI cutaneous) injection of Arlidin
produced a marked decrease of
VH systemic pressure in the intact
HC-CH3 dog. The depression of the blood
pressure is believed to be due to
CH2 a stimulation of B-adrenergic

 

HCI H
<:::::>"“C 2 receptors (14). Maxwell 21, a1,

(33) have observed a substantial
direct increase in cardiac output when 5 mg of Arlidin was injected

into the right atrium of dogs. The increase in cardiac output was

due to an increase in cardiac frequency while stroke volume decreased.

Systemic pressure and calculated total peripheral resistance also
decreased with generalized administration of Arlidin. The vaso-
dilation produCed by the drug must be greater than the increase in
cardiac output thus resulting in a decrease in systemic pressure.
Frohlich (14) has shown that a local infusion of l.2-49.4 ug/min

of Arlidin into the brachial artery of the dog has resulted primarily

in an active decrease in small vessel resistance in a constant flow

 

1 f" .

 

59

preparation. Arlidin has been demonstrated to be absorbed in
the gastrointestinal tract where it undergoes slow destruction.
It is slowly destroyed in the liver. This drug may produce a

prolonged action which may be due to this slow destruction (l3).

 

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